KR20230110558A - Treatment for brain metastatic tumors containing condensed pyrimidine compounds as active ingredients - Google Patents

Abstract

An object to be solved by the present invention is to provide a brain transitive antitumor agent exhibiting excellent brain transitability and RET inhibitory activity. The present invention provides a brain transitive antitumor agent comprising as an active ingredient a compound represented by the following general formula (I) (wherein R ¹ , R ² and R ³ are as described in the specification) or a salt thereof.

Description

Treatment for brain metastatic tumors containing condensed pyrimidine compounds as active ingredients

[Cross Reference to Related Applications]

This application claims priority based on the specification of Japanese Patent Application No. 2020-193073 filed on November 20, 2020 (the entire disclosure of which is incorporated herein by reference). The present invention relates to antitumor agents.

A brain tumor is one of the diseases of the brain, and means a tumor that occurs in an intracranial tissue. Brain tumors are divided into primary brain tumors, which occur in brain cells, and metastatic brain tumors, which are formed when cancers such as lung cancer and breast cancer metastasize to the brain. Symptomatic metastatic brain tumors are reported to occur in 8-10% of cancer patients, and in lung cancer, there are also reports that brain metastases are reported with a frequency of 40-50% at autopsy (Non-Patent Documents 1 to 3). Lung cancer, breast cancer, digestive system cancer (stomach cancer), malignant melanoma, renal urinary system, etc. are known as primary sources of metastatic brain tumors, and lung cancer accounts for about half of them (Non-Patent Document 2). In metastatic brain tumors, treatment varies depending on the systemic condition, tumor size, number of metastases, and the like. As treatment, radiation therapy, surgery, drug therapy, or a combination thereof is performed. In general, surgery is selected when the primary site is controlled, it is single, and a certain degree of survival is expected. However, in many cases, tumors that have metastasized into the brain are intricately intertwined with brain parenchyma and/or cranial nerve tissue, and in many cases, only the tumor cannot be completely resected by surgery. In radiation therapy, two treatments are known: quantitative radiosurgery treatment (eg, gamma knife therapy) and whole-brain irradiation in which radiation is irradiated to the entire brain. Most of the current metastatic brain tumor treatments are performed by combining surgery and radiation therapy, but it is difficult to say that sufficient therapeutic effects are exhibited (Non-Patent Documents 4 and 5). In general, the central nervous system (CNS) including the brain is protected from harmful substances by a tightly coupled layer of highly specialized cells called the blood brain barrier (BBB). One of the reasons why effective drugs have not been developed for most CNS-related diseases is that almost all therapeutic molecules including antibodies cannot cross the BBB. Low-molecular-weight compounds are no exception, and there is also a report that a low-molecular-weight compound exceeding 98% cannot pass through the BBB (Non-Patent Document 6). Currently, there are many compounds that show efficacy in peripheral cancer (primary site), but in the brain metastasis of the cancer, the efficacy is limited. It is considered that one of the reasons is that these compounds do not reach a sufficient amount to exert an effect in the brain and do not exhibit the same effect as the primary source (Non-Patent Documents 7 and 8). Therefore, in CNS-related diseases and brain tumors, the development of small-molecular compounds having high brain transitability and brain transit methods thereof are desired, and particularly in the treatment of metastatic brain tumors, lung cancer. A drug that exhibits an effective effect on primary sites such as lung cancer and exhibits high CNS transitivity and also exhibits effects on brain metastases is required.

For example, there are many compounds that show efficacy in the primary site, and compounds having RET inhibitory activity and the like are exemplified. Here, RET is a receptor-type tyrosine kinase identified as one of the proto-oncogenes, and binds to Glial cell-Derived 　 Neurotrophic 　 Factor (GDNF) and GDNF receptors to form complexes, thereby exerting physiological functions through intracellular phosphorylation signals (Non-Patent Document 9). In normal tissue, it has been reported that it contributes to the growth and nerve formation in the embryonic period (Non-Patent Document 10). In addition, in lung cancer, thyroid cancer, breast cancer, pancreatic cancer, prostate cancer, etc., it has been reported that RET is translocated, mutated, or overexpressed, and the activation state is enhanced, contributing to cell proliferation, tumor formation, or tissue invasion (Non-Patent Documents 11 to 16). In addition, it has been reported that RET translocation and activation level enhancement in these cancers are negatively correlated with prognosis (Non-Patent Documents 17 to 19), and RET is also known as a cancer prognostic factor.

Therefore, inhibitors capable of controlling the activity of RET are considered to be useful as therapeutic drugs for diseases associated with abnormal enhancement of the RET signaling pathway.

For example, in cancers in which RET is activated by translocation, mutation, or overexpression, it is expected that by administering a drug that specifically inhibits RET, it will be possible to selectively and intensively suppress the proliferation of cancer cells, and it is expected to contribute to the treatment, prolongation of life, and improvement of QOL of cancer patients.

As a compound having RET inhibitory activity, known compounds are known. For example, PP1 (Non-Patent Document 20) is known. PP1 has a structure in which a p-toluyl group is bonded to a condensed pyrimidine backbone. In addition to RET, PP1 is known to exhibit high inhibitory activity against Src (Non-Patent Document 21), c-Kit, Bcr-Abl (Non-Patent Document 22, 23) and the like. For example, there is a concern that inhibition of Src may cause hyperosseous abnormalities as a side effect, and inhibition of Lck may cause T cell suppression as a side effect (Non-Patent Documents 24 and 25). In this way, multi-kinase inhibitors are concerned about various side effects in order to inhibit cell proliferation by inhibiting various signal pathways in addition to RET, and if a reduction in dosage and / or withdrawal period is required due to side effects, there is a possibility that the RET inhibitory activity cannot be sufficiently exerted. From the viewpoint of reducing side effects, a RET inhibitor having high inhibitory activity against RET and low inhibitory activity against other kinases is desired. However, until now, there has been no report of a drug that exhibits a strong RET inhibitory effect and exhibits good cerebral transit.

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An object of the present invention is to provide a brain transitive antitumor agent exhibiting excellent brain transitability and RET inhibitory activity. An object of the present invention is to provide use of a compound or a salt thereof for producing a brain transitive antitumor agent exhibiting excellent brain transitivity and RET inhibition and antitumor effects, or for treating tumors using the brain transit antitumor agent. Another object of the present invention is to provide a method for treating tumors, particularly brain tumors, characterized by administering a brain transitive antitumor agent comprising a compound having RET inhibitory activity or a salt thereof.

As a result of intensive studies to solve the above problems, the inventors of the present invention found that a condensed pyrimidine compound or a salt thereof having a specific structure that selectively inhibits RET is useful as a brain transiting antitumor agent, and completed the present invention.

That is, the present invention includes the following embodiments.

[1] The following general formula (I)

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.) A brain transitive anti-tumor agent containing a compound represented by or a salt thereof as an active ingredient.

[2] The substituent of the C3-C5 cycloalkyl group which may have a substituent represented by R ² is (1-1) a C1-C2 alkyl group

Phosphorus, the brain transitive antitumor agent described in [1].

[3] The brain transitive antitumor agent according to [1] or [2], wherein R ² is a C3-C4 cycloalkyl group which may have a methyl group as a substituent.

[4] The substituent of the C2-C6 alkynyl group, which may have a substituent represented by R ³ ,

(2-1) Amino group which may have a substituent;

(2-2) C1-C6 alkyl group which may have a substituent;

(2-3) a 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may have substituents; or

(2-4) 4 to 10 membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms which may have substituents

phosphorus, the brain transitive antitumor agent according to any one of [1] to [3].

[5] The substituent of the C1-C6 alkoxy group, which may have a substituent represented by R ³ ,

(3-1) amino group;

(3-2) C1-C6 alkyl group which may have a hydroxyl group;

(3-3) a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group; or

(3-4) A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group.

phosphorus, the brain transitive antitumor agent according to any one of [1] to [4].

[6] R ¹ is a C1-C6 alkoxy C1-C6 alkyl group,

R ² is a C3-C5 cycloalkyl group which may have a C1-C2 alkyl group as a substituent;

R ³ is;

C2-C6 alkynyl group which may have a substituent; or

C1-C6 alkoxy group which may have a substituent

Phosphorus, the antitumor agent according to any one of [1] to [5].

(The substituent of the C2-C6 alkynyl group, which may have a substituent represented by R ³ ,

amino group;

C1-C6 alkyl group which may have at least 1 sort(s) selected from the group which consists of a hydroxyl group, an amino group, and a cyano group as a substituent;

As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group and a cyano group, and a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or

As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group, and a cyano group, and is a 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.

The substituent of the C1-C6 alkoxy group which may have a substituent represented by R ³ is

amino group;

C1-C6 alkyl group which may have a hydroxyl group;

A 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group; or

A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group, and an amino group.)

[7] The compound represented by the general formula (I) or a salt thereof,

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(7) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(14) 4-amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

Or the brain transition antitumor agent according to any one of [1] to [6], which is a salt thereof.

[8] The compound represented by the general formula (I) or a salt thereof,

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

The brain transitive antitumor agent according to any one of [1] to [7], which is or a salt thereof.

[9] The brain transitive antitumor agent according to any one of [1] to [8] for treating a primary or metastatic brain tumor.

[10] The following general formula (I) for preparing a brain transitive antitumor agent

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

Use of a compound represented by or a salt thereof.

[11] the following general formula (I)

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.) A method for treating a subject having a tumor, comprising administering to the subject in need of treatment a brain transitive antitumor agent comprising an effective amount of a compound represented by or a salt thereof.

[12] For use in the treatment of tumors by brain transitive antitumor agents, the following general formula (I)

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.) A compound represented by or a salt thereof.

[13] The following general formula (I) for treating tumors with brain transitive antitumor agents

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

Use of a compound represented by or a salt thereof.

[14] the following general formula (I) as an active ingredient

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

A commercial package comprising the compound represented by or a salt thereof together with instructions for its use for treating a tumor in a subject with a brain transitive antitumor agent.

[15] the following general formula (I)

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

A brain transitive antitumor agent for treating a tumor in which the activation state of RET is promoting, containing as an active ingredient the compound represented by or a salt thereof.

[16] The following general formula (I) for producing a brain transitive antitumor agent for treating tumors in which RET activation is promoted

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

Use of a compound represented by or a salt thereof.

[17] The following general formula (I) in an effective amount for a subject having a tumor in which the activation state of RET is increasing

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

A method for treating the subject, comprising administering a brain transitive antitumor agent comprising a compound represented by or a salt thereof.

[18] The following general formula (I) for use in the treatment of tumors in which the activation state of RET is enhanced by a brain transitive antitumor agent

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

A compound represented by or a salt thereof.

[19] The following general formula (I) for treating tumors in which the RET activation state is promoted by brain-transit antitumor agents

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

Use of a compound represented by or a salt thereof.

[20] the following general formula (I) as an active ingredient

(In the expression,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent;

R ³ is hydrogen;

A C2-C6 alkynyl group which may have a substituent, or

It is a C1-C6 alkoxy group which may have a substituent.)

A commercial package comprising the compound represented by or a salt thereof together with instructions for its use for treating a tumor in which the RET activation state in a subject is increasing with a brain transitive antitumor agent.

According to the present invention, an antitumor agent having brain transit properties is provided. According to a preferred aspect of the present invention, a novel therapeutic agent having a RET inhibitory action, which has an effective therapeutic effect for brain tumors, is provided. In addition, since the brain transitive antitumor agent of the present invention has an inhibitory effect with high selectivity for RET, it is expected to reduce toxicity by inhibiting other kinases and is useful because a high therapeutic effect can be expected.

Figure 1 shows the antitumor effect of the compound of the present invention in a brain transplantation model animal (NIH/3T3_CCDC6-RET brain transplantation model).
Figure 2 shows the body weight change rate of the compound of the present invention in a brain transplantation model animal (NIH/3T3_CCDC6-RET brain transplantation model).

One embodiment of the present invention relates to a brain transitive antitumor agent comprising a compound represented by the following general formula (I) or a salt thereof as an active ingredient.

In the present invention, the compound represented by general formula (I) may be simply referred to as compound (I).

In the present invention, the brain transitive antitumor agent means an antitumor agent intended to bring about a therapeutic effect by transferring at least a part of an active ingredient to the brain.

In the present specification, as a "substituent", unless otherwise specified, for example, a deuterium atom, a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkoxyalkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an alkenyl group, an alkynyl group, an amino group, a mono- or dialkylamino group, an oxo group, a saturated or unsaturated heterocyclic group (the saturated or unsaturated heterocyclic group is a C1-C6 alkyl group, a hydroxyl group, an amino group as a substituent) and at least one selected from the group consisting of cyano groups), aromatic hydrocarbon groups, and the like. When the said substituent exists, the number is not limited, but it is typically 1, 2, or 3. In this specification, when a plurality of substituents exist, the substituents may be the same or different unless otherwise specified.

In the present specification, when there are a plurality of substituent options for each group defined in the general formula (I), the substituents for each group may be of the same type or different types unless otherwise specified. For example, "an alkyl group having a halogen atom or a hydroxyl group as a substituent" includes an alkyl group having only a halogen atom and an alkyl group having only a hydroxyl group, as well as an alkyl group having both a halogen atom and a hydroxyl group, unless otherwise specified. In addition, "an alkyl group having a halogen atom or a hydroxyl group as a substituent" includes, for example, an alkyl group having two or more kinds of halogen atoms (eg, a fluorine atom and a chlorine atom).

In this specification, as a "halogen atom", a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned.

As used herein, "alkyl group" refers to a linear or branched chain saturated hydrocarbon group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, 1-methylpropyl group, n-pentyl group, isopentyl group, tert-pentyl group, pentan-3-yl group, n-hexyl group, 1,1-dimethylpropyl group, 1,1, 2,2-tetramethyl ethyl group, n-heptyl group, 1,1,2,2-tetramethylpropyl group, n-octyl group, n-nonyl group, n-decyl group and the like, C1-C10 alkyl group, C3-C10 alkyl group, C1-C6 alkyl group, C1-C4 alkyl group, C3-C8 alkyl group, C3-C6 alkyl group and the like are included.

In the present specification, "alkoxy group" refers to an oxy group to which the above-mentioned alkyl group is bonded, and includes, for example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, etc., and includes C1-C6 alkoxy group and C1-C4 alkoxy group.

In the present specification, "alkoxyalkyl group" refers to the above-described alkyl group having one or a plurality of alkoxy groups (for example, 1 to 5, preferably 1 to 3, more preferably 1), and examples thereof include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, n-butoxymethyl group, 2-methoxyethyl group, 1-methoxy-n-propyl group, 3-methoxy- n-propyl group, 2-ethoxy-n-butyl group, 4-methoxy-n-butyl group, 5-methoxy-n-pentyl group, 6-methoxy-n-hexyl group, etc., C1-C6 alkoxy C1-C6 alkyl group, C1-C4 alkoxy C1-C6 alkyl group, C1-C4 alkoxy C1-C4 alkyl group, etc. are included.

In the present specification, "C1-C6 alkoxyalkyl group" refers to an alkyl group to which the above C1-C6 alkoxy group is bonded, and examples include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, n-butoxymethyl group, 2-methoxyethyl group, 1-methoxy-n-propyl group, 3-methoxy-n-propyl group, 2-ethoxy-n-butyl group, and 4-methoxy-n-butyl group. , 5-methoxy-n-pentyl group, 6-methoxy-n-hexyl group, 8-methoxy-n-octyl group, etc. are mentioned.

In the present specification, "cycloalkyl group" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) saturated hydrocarbon group, and examples include monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups, spiro[3.3]heptyl group, spiro[3.4]octyl group, dispiro[5.1.78.26]heptadecanyl group, etc. polycyclic cycloalkyl groups of , and the like, and include C3-C7 cycloalkyl groups, C3-C5 cycloalkyl groups, and the like.

In the present specification, "aromatic hydrocarbon group" is a monocyclic or polycyclic (e.g., bicyclic, tricyclic) cyclic substituent composed of carbon atoms and hydrogen atoms having an unsaturated bond, and represents a substituent containing 4e+2 (e is an integer of 1 or more) electrons in the π electron system of the annular ring, and examples thereof include phenyl group, naphthyl group, anthracenyl group, phenanthryl group, fluorenyl group, and tetrahydronaphthyl group and aromatic hydrocarbon groups such as C6-C14, C6-C10, and C8-C14.

As used herein, the term "alkenyl group" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one double bond (eg, 1 to 2, 1, etc.), and includes, for example, a vinyl group, an allyl group, a 1-propenyl group, a 2-methyl-2-propenyl group, an isopropenyl group, a 1-, 2- or 3-butenyl group, a 2-, 3- or 4-pentenyl group, a 2- A methyl-2-butenyl group, a 3-methyl-2-butenyl group, a 5-hexenyl group, a 3-methyl-3-butenyl group, etc. are mentioned, and a C2-C6 alkenyl group, a C2-C4 alkenyl group, etc. are included.

As used herein, "alkynyl group" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one triple bond (eg, 1 to 2, 1, etc.), examples of which include an ethynyl group, a 1- or 2-propynyl group, a 1-, 2- or 3-butynyl group, a 1-methyl-2-propynyl group, and the like, a C2-C6 alkynyl group, a C2-C 4 alkynyl groups, etc. are included.

In the present specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic (eg bicyclic, tricyclic) saturated heterocyclic group containing one or a plurality (eg, 1 to 3) of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and examples thereof include morpholino group, 1-pyrrolidinyl group, 3-pyrrolidinyl group, piperidino group, and piperazine. Nyl group, 4-methyl-1-piperazinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothiophenyl group, thiazolidinyl group, oxazolidinyl group, thiomorphonyl group, 7-azabicyclo[2.2.1]hept-2-yl group, 2,6-dioxabicyclo[3.2.1]oct-7-yl group, 7-oxabicyclo[ 2.2.1] heptane group, etc., and 4-6 membered, 4-10 membered, 8-14 membered, 8-10 membered, etc. saturated heterocyclic groups are included.

In the present specification, "unsaturated heterocyclic group" refers to a monocyclic or polycyclic (eg bicyclic, tricyclic) fully unsaturated or partially unsaturated heterocyclic group containing one or a plurality (eg, 1 to 3) of the same or different heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and includes, for example, imidazolyl group, thienyl group, furyl group, pyrrolyl group, oxazolyl group, and isooxa. Zolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridinyl group, pyrazyl group, pyrimidinyl group, pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, triazolopyridinyl group, benzoimidazolyl group, benzooxazolyl group, benzothiazolyl group, benzothienyl group , a benzofuranyl group, a purinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group, a dihydrothiazolyl group, a benzothiophenyl group, and the like, and an unsaturated heterocyclic group having 4 to 6 members, 4 to 10 members, 8 to 14 members, and 8 to 10 members. included

In description of a substituent in this specification, "Ca-Cb" represents a substituent having a to b carbon atoms. For example, "C1-C6 alkyl group" represents an alkyl group having 1 to 6 carbon atoms, and "C6-C14 aromatic hydrocarbon oxy group" represents an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is bonded. Further, "members a to b" indicate that the number of atoms constituting the ring (reduced number) is a to b. For example, "4- to 10-membered saturated heterocyclic group" means a saturated heterocyclic group having 4 to 10 reducing numbers.

Although the following can be illustrated as a specific compound used as an active ingredient of the brain transit antitumor agent of this invention, It is not limited to these. Hereinafter, substituents such as R ¹ , R ² , and R ³ in the general formula representing Compound (I) will be specifically explained. When explaining the said substituent, unless otherwise specified, substituents, such as ^R1 , ^R2 , ^R3 , represent these substituents in General formula (I).

R ¹ is a C1-C6 alkoxyalkyl group.

The "C1-C6 alkoxyalkyl group" represented by R ¹ includes those described above, but is preferably a C1-C4 alkoxyalkyl group, more preferably a methoxymethyl group.

Examples of the “substituent” in the “C3-C5 cycloalkyl group which may have a substituent” represented by R ² (in this specification, the “substituent” in the “C3-C5 cycloalkyl group which may have a substituent” represented by R ² may be referred to as “substituent R ^A ”) include, for example, those described above as examples of the “substituent”, but preferably a C1-C6 alkyl group, more preferably It is a C1-C3 alkyl group, and more preferably a methyl group.

Examples of the “C3-C5 cycloalkyl group which may have a substituent” represented by R ² include the C3-C5 cycloalkyl group with or without the substituent R ^A , preferably a C3-C4 cycloalkyl group, more preferably a propyl group.

Examples of the "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ include those described above, preferably a C2-C4 alkynyl group, more preferably an ethynyl group or a propynyl group.

The number of triple bonds in the “C2-C6 alkynyl group” in the “C2-C6 alkynyl group which may have a substituent” is preferably one, and the position is preferably 7H-pyrrolo [2,3-d] It is preferably between a carbon atom bonded to the pyrimidine skeleton and a carbon atom adjacent to the carbon atom.

As the "substituent" in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ (in this specification, the "substituent" in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ may be referred to as "substituent R ^B "), preferably:

Amino group which may have a substituent;

C1-C6 alkyl group which may have a substituent;

a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent; or

A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent.

etc. can be mentioned.

As "substituent R ^B ", more preferably,

amino group

A straight-chain or branched C1-C6 alkyl group which may have substituents;

A 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent, or

A 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent,

More preferably,

amino group;

C1-C6 alkyl group which may have at least 1 sort(s) selected from the group which consists of a hydroxyl group, an amino group, and a cyano group as a substituent;

As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group and a cyano group, and a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or

As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group, and a cyano group, and is a 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.

Even more preferably,

amino group;

As a substituent, C1-C6 alkyl group which may have a hydroxyl group;

As the substituent, a 5- or 6-membered monocyclic saturated heterocyclic group which may have a C1-C6 alkyl group and contains 1 or 2 heteroatoms of nitrogen atoms; or

As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group and an amino group, and a 5- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 2 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom

am.

Preferable examples of the “substituent” in the “amino group which may have a substituent” described above as an example of the substituent (substituent R ^B ) in the “C2-C6 alkynyl group which may have a substituent” represented by R ³ include a C1-C6 alkyl group and a hydroxyl group.

As an example of the substituent (substituent R ^B ) in the “C2-C6 alkynyl group which may have a substituent” represented by R ³ , in the “C1-C6 alkyl group which may have a substituent” described above, preferable examples of the “substituent” include a hydroxyl group, a C1-C6 alkoxy group, or an oxo group, preferably a hydroxyl group.

In the "straight-chain or branched C1-C6 alkyl group which may have a substituent" described above as an example of the substituent (substituent R ^B ) in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ , the "C1-C6 alkyl group" is preferably a branched C1-C6 alkyl group, more preferably a branched C3-C6 alkyl group.

As an example of the substituent (substituent R ^B ) in the "optionally substituent C2-C6 alkynyl group" represented by R ³ , the aforementioned "optionally substituent C1-C6 alkyl group" is preferably a hydroxybutyl group.

As an example of the substituent (substituent R ^B ) in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ , preferable examples of the "substituent" of the "4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may have a substituent" described above are C1-C6 alkyl groups, hydroxyl groups, and amino groups. , or a cyano group, preferably a C1-C6 alkyl group, more preferably a methyl group.

As an example of the substituent (substituent R ^B ) in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ , the above-described "4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may have a substituent" described above is preferably a "substituent which may have a substituent of the same type selected from a nitrogen atom, an oxygen atom and a sulfur atom" or a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 to 2 hetero atoms,

More preferably, it is "a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 to 2 nitrogen atom heteroatoms which may have a substituent" (when it has a substituent, the substituent represents a methyl group),

More preferably, it is a morpholino group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, pyrrolidinyl group, piperidinyl group, thiomorpholinyl group, or oxetanyl group (when it has a substituent, the substituent represents a methyl group, an ethyl group, or an amino group), which may have a substituent.

More preferably, it is a morpholino group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, pyrrolidinyl group, piperidinyl group, or thiomorpholinyl group which may have a substituent (in the case of having a substituent, the substituent preferably represents a methyl group or an ethyl group, more preferably a methyl group).

The number of substituents is not particularly limited in the above-mentioned “4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent,” described above as an example of the substituent R ^B , but the number of substituents is not particularly limited, but is preferably 0 to 3, and more preferably 0 to 2.

As an example of the substituent (substituent R ^B ) in the "C2-C6 alkynyl group which may have a substituent" represented by R ³ , preferable examples of the "substituent" of the "4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may have a substituent" described above are C1-C6 alkyl groups, amino groups, and hydroxyl groups. , or a cyano group, preferably a C1-C6 alkyl group or an amino group, more preferably a methyl group or an amino group.

The "4 to 10 membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent,"

Preferably, it is "a 4 to 10 membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent" (the substituent represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or an amino group),

More preferably, it is "a 4 to 6 membered monocyclic unsaturated heterocyclic group containing 1 to 3 nitrogen atom heteroatoms which may have a substituent" (the substituent represents a C1-C6 alkyl group or an amino group),

More preferably, it is a pyrazolyl group, an imidazo[1,2-b]pyridazinyl group, an imidazolyl group, a pyridinyl group, a thiazolyl group, or a furo[3,2-b]pyridinyl group (the substituent represents a methyl group, an ethyl group, or an amino group), which may have a substituent.

Even more preferably, it is a pyrazolyl group, an imidazolyl group, or a pyridinyl group (the substituent represents a methyl group, an ethyl group, or an amino group, preferably a methyl group or an amino group), which may have a substituent.

As an example of the substituent R ^B , the number of substituents is not particularly limited in the “4 to 10 membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent,” described above, but is preferably 0 to 3, and more preferably 0 to 2.

In this specification, the "substituent" in the "C1-C6 alkoxy group which may have a substituent" represented by R ³ may be expressed as "substituent ^RC ".

The "C1-C6 alkoxy group which may have a substituent" represented by R ³ is

Preferably, the substituent R ^C is a C1-C6 alkoxy group which may have "a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group", more preferably,

Substituent R ^C is a C1-C6 alkoxy group which may have "a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms".

Examples of the substituent R ^C described above include "4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms", preferably "4 to 6 membered monocyclic saturated heterocyclic groups containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms", more preferably "acid A 4- to 6-membered monocyclic saturated heterocyclic group containing one small atom", and more preferably a "5-membered monocyclic saturated heterocyclic group containing one oxygen atom".

The "C1-C6 alkoxy group which may have a substituent" represented by R ³ is preferably a C1-C6 alkoxy group which may have "a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom" as the substituent R ^C ;

More preferably, the substituent R ^C is a C1-C4 alkoxy group which may have "a 4 to 6 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom",

More preferably, the substituent R ^C is a C1-C4 alkoxy group which may have "a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen atom",

More preferably, it is a methoxy group, an ethoxy group, a tetrahydrofuranyl methoxy group, a tetrahydropyranyl methoxy group, a tetrahydrofuranyl ethoxy group, or a tetrahydropyranyl ethoxy group.

More preferably, it is an ethoxy group or tetrahydrofuranyl methoxy group.

The number of substituents is not particularly limited, but is preferably 0 to 3, more preferably 0 to 2.

Examples of the "substituent" in the case where each group represented by R ³ has a substituent include those described above, and the number is typically 1, 2 or 3.

The "C1-C6 alkoxy group" in the "C1-C6 alkoxy group which may have a substituent" represented by R ³ includes those described above,

Preferably a C1-C4 alkoxy group,

More preferably, it is a methoxy group or an ethoxy group.

In one embodiment, the compound represented by general formula (I) or a salt thereof,

R ¹ is a C1-C6 alkoxyalkyl group;

R ² is a C3-C5 cycloalkyl group which may have a substituent R ^A ;

R ³ is;

hydrogen,

A C2-C6 alkynyl group which may have a substituent R ^B , or

It is a C1-C6 alkoxy group which may have substituent R ^C .

In one embodiment, the compound represented by general formula (I) or a salt thereof,

R ¹ is a C1-C3 alkoxyalkyl group;

R ² is a C3 cycloalkyl group which may have a substituent R ^A ;

R ³ is;

A C2-C3 alkynyl group which may have a substituent R ^B , or

It is a C1-C2 alkoxy group which may have substituent R ^C .

In one embodiment, the compound represented by formula (I) or a salt thereof

R ¹ is a methoxymethyl group;

R ² is a methylcyclopropyl group;

R ³ is hydrogen,

a propynyl group which may be substituted with a morpholino group, a dimethylamino group, a piperidinyl group, a pyrrolidinyl group, a branched propanol group, or a 3-thiomorphonyl group;

an ethynyl group which may be substituted with a 1,3-dimethylpyrazolyl group, a 1-methylpiperidinyl group, a 1-methylpyrazolyl group, a 1-methylimidazolyl group, a pyridinyl group, or a 6-aminopyridinyl group;

an ethoxy group, or

tetrahydrofuranylmethoxy group

am.

In one embodiment, the compound represented by general formula (I) or a salt thereof,

R ¹ is a methoxymethyl group;

R ² is a methylcyclopropyl group;

R ³ is;

A propynyl group which may be substituted with a morpholino group, a dimethylamino group, a piperidinyl group, a pyrrolidinyl group, a branched propanol group, a 3-thiomorpholino group, or a tetrahydropyranyl group;

an ethynyl group which may be substituted with a 1,3-dimethylpyrazolyl group, a 1-methylpiperidinyl group, a 1-methylpyrazolyl group, a 1-methylimidazolyl group, a pyridinyl group, a 6-aminopyridinyl group, or a tetrahydropyranyl group;

an ethoxy group, or

tetrahydrofuranylmethoxy group

am.

In one embodiment, the compound represented by general formula (I) or a salt thereof,

R ¹ is a methoxymethyl group;

R ² is a methylcyclopropyl group;

R ³ is;

a propynyl group which may be substituted with a morpholino group, a dimethylamino group, or a pyrrolidinyl group;

an ethynyl group which may be substituted with a 1,3-dimethylpyrazolyl group, a 1-methylpyrazolyl group, a pyridinyl group, or a tetrahydropyranyl group;

ethoxy group

am.

As one embodiment, the compound represented by the general formula (I) or a salt thereof,

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(7) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(14) 4-amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

or a salt thereof.

As one embodiment, the compound represented by the general formula (I) or a salt thereof,

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

or a salt thereof.

In addition, the present invention is a RET inhibitor containing compound (I) or a salt thereof (for example, a compound described as an active ingredient of the brain transit antitumor agent described in any of the above [1] to [9] or a salt thereof. The same applies hereinafter) as an active ingredient, a method for treating a subject having a tumor, comprising administering to the subject in need of treatment a brain transitive antitumor agent containing an effective amount of compound (I) or a salt thereof; a commercial package containing Compound (I) or a salt thereof as an active ingredient together with instructions for its use for treating a tumor in a subject with a brain transitive antitumor agent; A brain transitive antitumor agent comprising compound (I or a salt thereof as an active ingredient for treating a tumor in which RET activation status is intensifying; a method for treating a subject having a tumor in which RET activation status is intensifying; comprising administering an effective amount of a brain transition antitumor agent containing compound (I) or a salt thereof to a subject having a tumor in which RET activation status is intensifying; a tumor in which RET activation status in a subject is intensified with a compound represented by compound (I) or a salt thereof or a salt thereof as an active ingredient. Commercial package, including with instructions for its use for treatment by brain transitive antitumor agents, etc.

provides

Compound (I) and salts thereof can be prepared according to known organic synthesis methods. For example, it can manufacture according to the method described in international publication WO2017/146116 gazette etc.

When Compound (I) has isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, both isomers and mixtures are included in Compound (I) unless otherwise specified. For example, when compound (I) has optical isomers, compound (I) also includes racemates and optical isomers separated from racemates, unless otherwise specified.

The salt of Compound (I) means a pharmaceutically acceptable salt, and includes base addition salts and acid addition salts.

A "pharmaceutically acceptable salt" is a salt having a desired pharmacological activity of a compound, and means a salt prepared with a pharmaceutically acceptable non-toxic base or acid containing inorganic or organic bases and inorganic or organic acids.

Specific examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, and glutamic acid; salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; or salts with basic amino acids such as lysine, arginine, ornithine; and ammonium salts.

Compound (I) or its salt includes its prodrug. A prodrug refers to a compound that is converted to Compound (I) or a salt thereof by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound that is converted to Compound (I) or a salt thereof by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is hydrolyzed by gastric acid or the like to be converted to Compound (I) or a salt thereof. In addition, it may change to Compound (I) or a salt thereof under physiological conditions described in Hirokawa Shoten, 1990 "Development of Pharmaceuticals" Volume 7 Molecular Design, pages 163 to 198.

Compound (I) or a salt thereof may be amorphous (amorphous body) or may be a crystal, and whether the crystal form is single or a polymorphic mixture is included in Compound (I) or a salt thereof. Crystals can be produced by crystallization by applying a known crystallization method. Compound (I) or a salt thereof may be a solvate (for example, a hydrate) or a non-solvate, and all are included in Compound (I) or a salt thereof. Compounds labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also included in Compound (I) or salts thereof. Although a plurality of crystals (crystal polymorphs) with spatially regular arrangement of atoms and different physicochemical properties may be formed, the salt according to the present invention may be any of these crystal polymorphs, a mixture of two or more crystal polymorphs, or a mixture of a crystal and an amorphous body.

As used herein, the term "effective amount" of compound (I) refers to an amount (therapeutically effective amount) of compound (I) that causes a decrease or inhibition of a biological or medical response of a subject, for example, enzyme or other protein activity, or improves symptoms, relieves conditions, slows or delays the progression of a disease, or prevents a disease.

In the present specification, "treatment" includes postoperative adjuvant chemotherapy performed to prevent recurrence after surgical removal of a tumor, and preoperative adjuvant chemotherapy performed in advance to surgically extract a tumor.

In this specification, the term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, reptiles, and the like. In one embodiment, the subject is a mammal, particularly a human, and may be a human diagnosed in need of treatment for a symptom, condition, or disease disclosed herein.

The age of the subject to whom the therapeutic agent of the present invention is administered is not particularly limited. The therapeutic agent of the present invention can be used not only for adults but also for the elderly or children.

Because of its excellent RET inhibitory activity, Compound (I) or a salt thereof is useful as a medicament for preventing and/or treating RET-related diseases. "Diseases involved in RET" include diseases in which the onset rate is reduced, symptoms are relieved, alleviated, and/or cured by the deletion, suppression, and/or inhibition of RET functions. Examples of such diseases include, but are not limited to, malignant tumors and the like. The malignant tumor is preferably a malignant tumor in which the RET activation state is increased, more preferably salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colorectal cancer, rectal cancer, etc.), thyroid cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, brain tumor, more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, and colorectal cancer in which the RET activation state is increased. They are bowel cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumor. More particularly preferred are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer and brain tumor.

The enhancement of the activation state of RET indicates that the activation state of the RET gene is enhanced by translocation, mutation (including point mutations, deletion mutations, and insertion mutations) and overexpression (including states in which copy number of the RET gene increases, messenger RNA of RET is expressed excessively, RET protein increases, or RET protein is constitutively activated).

Target cancers and tumors are not particularly limited, but examples thereof include epithelial cancers (respiratory system cancers, digestive system cancers, reproductive system cancers, secretory system cancers, etc.), sarcomas, hematopoietic cell system tumors, central nervous system tumors, peripheral nerve tumors, and the like.

Specific carcinomas include head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, gastric cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder, cholangiocarcinoma, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), kidney cancer, renal pelvis/ureter cancer, bladder Examples include cancer, prostate cancer, testicular tumor, leukemia, malignant lymphoma, multiple myeloma, bone/soft tumor, skin cancer, malignant melanoma, adrenal tumor, and brain tumor. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, leukemia, skin cancer, malignant melanoma, and brain tumor. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, brain tumor, more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumor. Also particularly preferably, they are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumor.

In a typical embodiment of the present invention, the target tumor on which Compound (I) exhibits an effect by passing through the BBB is a brain tumor. In the present invention, brain tumors include primary brain tumors and metastatic brain tumors. Primary tumors are not particularly limited to the following, but include glioma (glioma), central nervous system primary malignant lymphoma, meningioma, pituitary adenoma, schwannoma, craniopharyngioma, and the like. In addition, among metastatic brain tumors, the type of tumor that became the primary source is not considered.

In the case of metastatic brain tumor, the type of primary tumor is not limited, but specific carcinomas include head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, stomach cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, and uterine cancer. (cervical cancer, cervical cancer, etc.), kidney cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, testicular tumor, leukemia, malignant lymphoma, multiple myeloma, bone/soft tissue tumor, skin cancer, malignant melanoma, and adrenal tumor. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, brain tumor, more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumor. Also particularly preferably, they are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumor.

The therapeutic agent of the present invention can provide the active ingredient alone. In addition to compound (I) or a salt thereof as an active ingredient, the therapeutic agent of the present invention may be formulated with a pharmaceutically acceptable carrier or the like as needed. Thus, the therapeutic agent of the present invention can be formulated as a pharmaceutical composition comprising one component or two or more components. One embodiment of the present invention provides a pharmaceutical composition containing compound (I) or a salt thereof. The pharmaceutical composition of one embodiment of the present invention contains compound (I) or a salt thereof and a pharmaceutically acceptable carrier. In addition, one embodiment of the present invention provides use of compound (I) or a salt thereof for preparing a therapeutic agent or pharmaceutical composition. Another embodiment of the present invention provides compound (I) or a salt thereof for use as a therapeutic agent or medicament.

The therapeutic agent of the present invention can be prepared as various dosage formulations according to known methods using pharmaceutically acceptable carriers, if necessary. The dosage form may be either oral or parenteral. There is no particular limitation on the form of such a formulation, and examples thereof include oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, and emulsions, and parenteral preparations such as injections, suppositories, and inhalants.

When molded into a tablet form, examples of pharmaceutically acceptable carriers include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, corn starch, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, and lactose; disintegration inhibitors such as white sugar, stearic acid, cacao butter, and hydrogenated oil; absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, milk sugar, kaolin, bentonite, and colloidal silicic acid; Lubricants, such as purified talc, stearic acid salt, boric acid powder, and polyethylene glycol, etc. can be used. In addition, the tablet may be a tablet subjected to a conventional coating, for example, a sugar-coated tablet, a gelatin coated tablet, an enteric coated tablet, a film-coated tablet, a double tablet, a multi-layer tablet, and the like, if necessary.

When molded in the form of a pill, examples of pharmaceutically acceptable carriers include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic, tragacanth, gelatin, and ethanol; Disintegrants such as laminaran and agar can be used. Capsules are prepared by mixing them with various pharmaceutically acceptable carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc., according to a conventional method.

In the case of oral liquid formulations, oral liquids, syrups, elixirs, etc. can be prepared in accordance with conventional methods using, for example, a flavoring or flavoring agent, a buffer, a stabilizer, etc. as a pharmaceutically acceptable carrier. In this case, saccharide, lamprey, citric acid, tartaric acid, etc. are mentioned as a flavoring/flavoring agent, sodium citrate etc. are mentioned as a buffering agent, and tragacanth, gum arabic, gelatin, etc. are mentioned as a stabilizer.

When molding in the form of a suppository, as pharmaceutically acceptable carriers, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used.

When used as an injection, it is preferable that solutions, emulsions and suspensions are sterile and isotonic with blood. In addition, when molding into these forms, a diluent can be used as a pharmaceutically acceptable carrier. As such a diluent, for example, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, macrogol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.

In this case, sodium chloride, glucose, or glycerin in an amount sufficient to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizing agent, buffer, analgesic agent, or the like may be added.

In the case of an inhalant, various forms such as an aerosol, a powder inhalant, and a liquid inhalant may be used.

Further, in each of the above preparations, as a pharmaceutically acceptable carrier, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, etc., and/or other pharmaceuticals may be blended as necessary.

In the present invention, the daily dose refers to the amount of the active ingredient administered per day. In the therapeutic agent of the present invention, the daily dosage of Compound (I) or a salt thereof on the day of administration varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined uniformly. For example, as compound (I), 10 to 2000 mg/day is usually preferable for an adult (body weight of 50 kg), more preferably 20 to 1500 mg/day, still more preferably 40 to 1200 mg/day.

In addition, the amount of Compound (I) to be blended in each of the above dosage unit forms is not constant depending on the symptoms of the patient to be applied or the dosage form thereof. In general, per dosage unit form, 0.05 to 1000 mg for oral preparations, 0.01 to 500 mg for injections, and 1 to 1000 mg for suppositories are preferred.

The method of administering the therapeutic agent of the present invention is appropriately determined depending on the type of preparation, the patient's age, sex and other conditions, the degree of the patient's symptoms, and the like. Although the administration method of the therapeutic agent of the present invention is not limited, it is preferable to use an administration method such that the active ingredient, Compound (I) or a salt thereof, is transferred to the brain through the systemic circulatory bloodstream in order to exhibit good cerebral transit. Examples of the administration method of the therapeutic agent of the present invention include oral administration, intravenous administration, intraarterial, intramuscular, intradermal, subcutaneous or intraperitoneal administration, intrarectal administration and the like. In the present invention, at least two of these administration methods may be combined. For example, tablets, pills, powders, granules, capsules, solutions, suspensions and emulsions are administered orally. Injections are administered intravenously either alone or mixed with normal supplements such as glucose and amino acids, and are administered intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. Suppositories are administered intrarectally.

In the present invention, "instruction" is, but is not particularly limited to, an attached document provided with a drug, an instruction displayed electronically, and a barcode or two-dimensional code for accessing the instruction in a box for storing the drug.

Hereinafter, the present invention will be described in more detail with examples, but the present invention is not limited thereto.

In addition, all documents and publications described in this specification are incorporated herein by reference in their entirety regardless of their purpose.

In addition, the objective, characteristic, advantage, and idea of this invention are clear to those skilled in the art from description of this specification, and anyone skilled in the art can implement this invention easily from description of this specification. The specific content and specific examples for carrying out the invention indicate preferred embodiments of the present invention, and are shown for illustration or explanation, and the present invention is not limited thereto. It is clear to those skilled in the art that various modifications can be made based on the description in this specification within the intent and scope of the present invention disclosed in this specification.

Example

In the following examples, % represents the mass percentage unless otherwise specified.

As for the various reagents used in Examples, commercially available products were used unless otherwise specified.

In addition, the meaning of abbreviation is shown below.

PBS: Phosphate Buffered Saline

LC-MS/MS: Liquid Chromatography Tandem Mass Spectrometer

HPMC: hydroxypropyl methylcellulose

Test Example 1 Evaluation of plasma protein binding and brain protein binding

The compounds shown in Tables 1 to 4 were added to mouse plasma to a final concentration of 1 µmol/L. The obtained compound-added mouse plasma was added to the donor side of a balanced dialysis device (HTDialysis) in which a balanced dialysis membrane was set. The same amount of PBS was added to the receiver side of the device, and after incubation in a 10% CO2 incubator for 6 hours, compounds on the donor side and receiver side were detected by LC-MS/MS. From the peak area ratio of the compound on the receiver side to the donor side, the non-binding ratio of the compound to plasma proteins was calculated.

The non-binding ratio of the compound to brain protein was calculated in the same manner as above except that the compound was added to mouse brain homogenate instead of mouse plasma and the dilution fraction was taken into account when calculating the non-binding ratio. Here, the mouse brain homogenate was obtained by homogenizing with an ultrasonic homogenizer after adding 3 times the amount of PBS to the mouse brain.

Test Example 2 Evaluation of Brain Transitivity

The compounds shown in Tables 1 to 4 were dissolved or suspended in 0.5% HPMC and 0.1 N hydrochloric acid solution, and single orally administered to untreated or BALB/cAJcl-nu/nu mice (Nippon Clea Co., Ltd.) transplanted subcutaneously with TT cells or subcutaneously transplanted with the BaF3/KIF5B-RET_RFP cell line. 1 hour after oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia, and then the whole brain was removed to obtain blood and brain samples. The obtained blood sample was centrifuged to obtain a plasma sample. After adding 3 times the amount of water to the obtained brain sample, it was homogenized using an ultrasonic homogenizer to obtain brain homogenate.

The compound concentrations in the obtained plasma and brain homogenate were measured by LC-MS/MS, and the compound concentration in brain was calculated by multiplying by a coefficient of 4. The Kp value was calculated from the compound concentration ratio in brain/plasma. Concentrations of unbound compounds in plasma and brain were calculated from the plasma protein unbound ratio and brain protein unbound ratio of each compound obtained in Test Example 1, and Kp and uu values were calculated from the brain/plasma unbound compound concentration ratio. Brain transition was evaluated from the calculated Kp values and Kp, uu values (Tables 1 to 4). Specifically, those with a Kp value of 0.1 or more were judged to have brain transitability, and those with Kp and uu values of 0.3 or more were judged to have good brain transitability (Varadharajan, S., et al. (2015) J Pharm Sci 104, 1197-1206). In Table 4, "N/A" of the Kp and uu values means that they were not measured.

From the results shown in Tables 1 to 4, it can be seen that Compound (I) exhibits high Kp values and Kp, uu values, and exhibits good brain transferability.

Test Example 3 Evaluation of drug efficacy in intracerebral tumor transplantation model

Anti-tumor evaluation was conducted in a model in which a tumor was transplanted into the brain. For the compounds shown in Examples 2 and 4 shown in Table 1 and Example 13 shown in Table 3, the growth inhibitory effect of transplanted tumors was confirmed.

For confirmation of the proliferation inhibitory action, NIH/3T3 cells (NIH/3T3_CCDC6-RET cells) in which luciferase and CCDC6-RET fusion protein were forcibly expressed by gene introduction were used. Six-week-old male nude mice (BALB/cAJcl-nu/nu, Nippon Clea) were fixed in a brain stereotaxic device, and 2.5 × 10 ⁴ cells per mouse were implanted at a site 0.5 mm anteriorly, 2 to 2.2 mm to the right, and 3.5 mm deep from the bregma. The implantation day was set as Day 0, and luciferin (150 mg/kg) was intraperitoneally administered on Day 4, and the amount of light emission (photons/sec) was measured using an IVIS Imaging System (Lumina II, PerkinElmer). The animals were assigned to 4 groups (N=10) so that the average amount of light emission in each group was about the same according to the measured light emission amount.

From the next day (Day 5), the compound was administered twice a day for 16 consecutive days. The compound was suspended in 0.5% HPMC/0.1 N hydrochloric acid and orally administered at 50 mg/kg/day. In order to confirm the growth of the tumor, the amount of light emission was measured at intervals of 3 or 4 days by the method described above.

The next day after the final administration (Day 21) was the final measurement day, and the tumor growth inhibitory effect of the compound was confirmed. However, in the drug-non-administration (control) group, the humane endpoint due to tumor growth was applied. Statistical evaluation was performed by Dunnett's test using the measured value on Day 14.

Changes in the amount of light emission over time are shown in Fig. 1, and changes in body weight are shown in Fig. 2. In the control group, an increase in the amount of light emission was confirmed, and it was thought that the transplanted tumor increased. In addition, weight loss, which is considered to be caused by tumor growth, was confirmed. Humane endpoints were applied because by Day 19 all animals showed weight loss and it was judged impossible to continue the test. On the other hand, in the compound administration group, no remarkable increase in the amount of light emission was observed in all compounds, and it was considered that tumor growth was suppressed. On Day 14, when statistical analysis was performed on the amount of light emission, a significant difference (*: p<0.05) was confirmed in all compound-administered groups compared to the control group. From these points, it was thought that there was a significant tumor growth inhibitory effect by administration of the compound. In addition, in the compound administration group, it was suggested that administration could be completed in all animals by Day 22, and that a life-sustaining effect could also be expected by compound administration.

From the above results, it was suggested that the growth of tumor cells transplanted into the brain was significantly inhibited by the administration of the compound exhibiting brain migration, and that a life-sustaining effect could also be expected.

Claims (19)

The following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.) A brain transitive anti-tumor agent containing a compound represented by or a salt thereof as an active ingredient. The substituent of the C3-C5 cycloalkyl group according to claim 1, which may have a substituent represented by R ² ,
(1-1) C1-C2 alkyl group
Phosphorus, a brain transitive antitumor agent. The brain transitive antitumor agent according to claim 1 or 2, wherein R ² is a C3-C4 cycloalkyl group which may have a methyl group as a substituent. The substituent of the C2-C6 alkynyl group according to any one of claims 1 to 3, which may have a substituent represented by R ³ ,
(2-1) Amino group which may have a substituent;
(2-2) C1-C6 alkyl group which may have a substituent;
(2-3) a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have a substituent; or
(2-4) 4 to 10 membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, which may have substituents
Phosphorus, a brain transitive antitumor agent. The substituent of the C1-C6 alkoxy group according to any one of claims 1 to 4, which may have a substituent represented by R ³ ,
(3-1) amino group;
(3-2) C1-C6 alkyl group which may have a hydroxyl group;
(3-3) a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group; or
(3-4) A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group.
Phosphorus, a brain transitive antitumor agent. 6. The compound according to any one of claims 1 to 5, wherein R ¹ is a C1-C6 alkoxy C1-C6 alkyl group;
R ² is a C3-C5 cycloalkyl group which may have a C1-C2 alkyl group as a substituent;
R ³ is;
C2-C6 alkynyl group which may have a substituent; or
C1-C6 alkoxy group which may have a substituent
Phosphorus, an antitumor agent.
(The substituent of the C2-C6 alkynyl group, which may have a substituent represented by R ³ ,
amino group;
C1-C6 alkyl group which may have at least 1 sort(s) selected from the group which consists of a hydroxyl group, an amino group, and a cyano group as a substituent;
As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group and a cyano group, and a 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; or
As a substituent, it may have at least one selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, an amino group, and a cyano group, and is a 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
The substituent of the C1-C6 alkoxy group which may have a substituent represented by R ³ is
amino group;
C1-C6 alkyl group which may have a hydroxyl group;
A 4 to 10 membered monocyclic saturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group and an amino group; or
A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, which may have at least one substituent selected from the group consisting of a methyl group, an ethyl group, and an amino group.) The compound represented by the general formula (I) or a salt thereof according to any one of claims 1 to 6,
(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(7) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazol-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(14) 4-amino-6-(4-hydroxy-4-methylpent-1-yn-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
or a salt thereof, a brain transitive antitumor agent. The compound represented by the general formula (I) or a salt thereof according to any one of claims 1 to 7,
(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinoprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
or a salt thereof, a brain transitive antitumor agent. The brain transitive antitumor agent according to any one of claims 1 to 8, for treating a primary or metastatic brain tumor. For the preparation of brain transitive antitumor agents, the following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
Use of a compound represented by or a salt thereof. The following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.) A method for treating a subject having a tumor, comprising administering to the subject in need of treatment a brain transitive antitumor agent comprising an effective amount of a compound represented by or a salt thereof. For use in the treatment of tumors by brain transitive antitumor agents, the following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.) A compound represented by or a salt thereof. For the treatment of tumors by brain transitive antitumor agents, the following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
Use of a compound represented by or a salt thereof. The following general formula (I) as an active ingredient

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
A commercial package comprising the compound represented by or a salt thereof together with instructions for its use for treating a tumor in a subject with a brain transitive antitumor agent. The following general formula (I)

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
A brain transitive antitumor agent for treating a tumor in which the activation state of RET is promoting, containing as an active ingredient the compound represented by or a salt thereof. The following general formula (I) for producing a brain transitive anti-tumor agent for treating a tumor in which the activation state of RET is increasing

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
Use of a compound represented by or a salt thereof. An effective amount of the following general formula (I) for a subject having a tumor in which the activation state of RET is increasing

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
A method for treating the subject, comprising administering a brain transitive antitumor agent comprising a compound represented by or a salt thereof. The following general formula (I) for use in the treatment of tumors in which the activation state of RET is promoted by a brain transitive antitumor agent

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
A compound represented by or a salt thereof. The following general formula (I) for treating tumors in which the activation state of RET is promoted by brain transitive antitumor agents

(In the expression,
R ¹ is a C1-C6 alkoxyalkyl group;
R ² is a C3-C5 cycloalkyl group which may have a substituent;
R ³ is hydrogen;
A C2-C6 alkynyl group which may have a substituent, or
It is a C1-C6 alkoxy group which may have a substituent.)
Use of a compound represented by or a salt thereof.